Bone formation is a complex process regulated by hormones and by systemic and local growth factors. Work from several laboratories, including our own, has shown that bone synthesizes growth factors which act as autologous regulators of bone remodeling. Recently, we have found that 21-day fetal rat calvariae synthesize a somatomedin (Sm) or insulin-like growth factor (IGF) and secrete SM-binding protein(s). Similarly, bovine bone matrix also contains SM and Sm-binding protein(s). Similarly, bovine bone matrix also contains Sm and Sm- binding protein(s). The Sm synthesized by calvarial cultures was characterized as a rat Sm C, and Sm is a major regulator of bone collagen and matrix synthesis. Sm synthesis by calvariae is likely regulated by systemic hormones and its effects modulated by Sm-binding protein(s). During the next five years we will study the hormonal regulation of Sm C synthesis in cultured rat calvarial cells by examining effects on Sm C concentrations, using a specific radioimmunoassay, and on Sm C-mRNA expression, using oligonucleotide probes and a rat Sm C-cDNA clone. Although Sm C is known as a major regulator of bone collagen synthesis, the mechanism of its effect has not been explored. For this purpose we will examine the effects of Sm C on type I collagen gene expression. Since the effects of calvarial Sm C are likely modulated by its binding protein(s), our investigations will be complemented by studies on the characterization, synthesis and biological effects of Sm-binding protein(s) obtained from cultured calvariae. This work is valuable because SM C has an important effect on bone remodeling and it is likely to mediate the effects or systemic hormones on bone. Our current understanding of bone cell physiology and metabolic bone disease is limited and this research may provide future diagnostic and therapeutic alternatives for metabolic bone disorders.